tbuckley/cabot-search huggingface dataset:
Abstract 5942: Vitamin D, calcium supplement use and the risk of breast cancer in <i>BRCA1</i> and <i>BRCA2</i> mutation carriers: A case-control study
Authors: Emma Guyonnet, Shana J. Kim, Cindy X. Zhang, Jeanna McCuaig, Susan Armel, Steven A. Narod, Joanne Kotsopoulos
Journal: Cancer Research (2022)

Abstract Background: Use of vitamin D and calcium-containing supplements are associated with a decreased risk of breast cancer among women in the general population. Whether this association exists among women at a high-risk due to a BRCA1 or BRCA2 mutation is not known. Thus, we conducted a case-control study to evaluate the association between vitamin D and/or calcium supplement use and the risk of breast cancer among BRCA mutation carriers. Methods: BRCA mutation carriers enrolled in a longitudinal study, that collected information on cancer history and lifestyle factors, were invited to complete a supplemental questionnaire on past supplement use. Vitamin D and calcium supplement use were categorized as never or ever use. Total average daily vitamin D and calcium use was stratified as never, moderate, or high intake based on tertiles. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) of invasive breast cancer associated with supplement use. Analyses were stratified by BRCA mutation type and menopausal status at breast cancer diagnosis. Results: This study included 134 cases and 276 controls. Compared to never users, ever vitamin D or calcium-containing supplement use was associated with decreased odds of breast cancer (OR=0.54; 95%CI 0.31, 0.91; P=0.02 for vitamin D; OR=0.61; 95%CI 0.36, 1.05; P=0.07 for calcium). The protective effect of vitamin D and calcium was stronger for those with the highest intake of each supplement (OR=0.44; 95% CI 0.22, 0.89; P=0.02 for vitamin D; OR=0.55; 95% CI 0.28, 1.08; P=0.08 for calcium), compared to never use. For vitamin D use, findings were significant among premenopausal women while for calcium use, the inverse associations were stronger among postmenopausal women. Findings were also significant for BRCA1 mutation carriers only, however, stratified analyses were limited by small strata. Conclusions: Although based on a relatively small sample, our findings suggest a potential protective effect of vitamin D and calcium-containing supplement use for breast cancer among high-risk women. Future studies with larger samples and prospective study design are warranted. Citation Format: Emma Guyonnet, Shana J. Kim, Cindy X. Zhang, Jeanna McCuaig, Susan Armel, Steven A. Narod, Joanne Kotsopoulos. Vitamin D, calcium supplement use and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5942.
Inspiratory hyperoxia suppresses lung cancer metastasis through a MYC/SLC1A5-dependent metabolic pathway
Authors: Xiucheng Liu, Hao Qin, Zheng Li, Yin Lv, Shoujie Feng, Wei Zhuang, Xiaoyu Quan, Chen Guo, Chang Chen, Hao Zhang
Journal: European Respiratory Journal (2022)

The lack of knowledge about the effect of inspiratory hyperoxia on the lung-specific tumour microenvironment and progression of lung cancer has attracted considerable attention. This study proposes that inspiratory hyperoxia has special significance for the malignant phenotype of lung cancer cells. The effects of different oxygenation parameters on the proliferation, apoptosis, invasion and migration of lung cancer cells were systematically evaluated in vitro and in vivo Our results reveal that inspiratory hyperoxia treatment (60% oxygen, 6 h·day-1) not only has no tumour progression-promoting effects, but also suppresses lung cancer metastasis and promotes long-term survival. In addition, we combined transcriptome, proteome and metabolome analysis and found that hyperoxia treatment induced significant intracellular metabolic changes in lung cancer cells. Overall, we established that MYC/SLC1A5-induced metabolic reprogramming and glutamine addiction is a new mechanism that drives lung cancer metastasis, which can be significantly suppressed by inspiratory hyperoxia treatment. These findings are relevant to the debate on the perils, promises and antitumour effect of inspiratory hyperoxia, especially for patients with lung cancer.
Abstract 3974: Investigating doxorubicin resistance in fibrosarcoma
Authors: Rodney Dixon Dorand, Donna Dang, Elizabeth J. Davis, Ben Ho Park
Journal: Cancer Research (2022)

Abstract Cytotoxic chemotherapy has been the backbone of medical oncology for nearly a century for multiple cancer types. However, when treating advanced or metastatic disease toxicity, side effects, and acquired resistance often limit the duration of therapy. While randomized control trials have traditionally served as the proving ground for first and subsequent line therapies, rare tumor subtypes including soft tumor sarcoma (STS) provide unique challenges for developing robust treatment data. By developing human based in vitro models, we can investigate potential therapeutic mechanisms for STS. Fibrosarcoma is one distinct histologic STS subtype that relies heavily on anthracycline treatment in the first line setting, however, there are limited options once resistance develops. Anthracyclines, including doxorubicin, exert their effect through a variety of mechanisms including reactive oxygen species, DNA-adduct formation, and inhibiting topoisomerase II, histone eviction, calcium and iron homeostasis, and ceramide overproduction. However, there have also been multiple mechanisms of doxorubicin resistance including disruption of cell membrane, alteration of cell surface molecules, inactivation of drugs, gene amplification, activating alternative signaling pathways, and affecting cellular repair mechanisms. In order to investigate the role of anthracycline resistance in fibrosarcoma lines we acquired two human derived fibrosarcoma lines SW684 and HT-1080 from American Type Culture Collection (ATCC). Characterization of HT-1080 using publicly available datasets demonstrated that TP53, CDK2NA and NF1 serve as major driver mutations while SW684 relies on NRAS and IDH1 mutations. We further characterized these cell lines in vitro and noted that HT-1080 has a quick doubling time of 16 hours while SW684 has a doubling time of 91 hours. Additionally, after doxorubicin treatment, we found that HT-1080 is sensitive with an IC50 of 5.594 nanomolar while SW684 is relatively doxorubicin resistant with an IC50 of 28.915 micromolar. While proliferative rate may play a role in the sensitivities of these cell lines further characterization of the mechanism leading to doxorubicin resistance is needed. To that end, we are using a CRISPR-Cas9 approach for further genome wide screening of these fibrosarcoma lines in the presence of doxorubicin. Exploring the genetic mechanisms that result in development of doxorubicin resistance may reveal novel, targetable mechanisms expanding treatment durability in this rare STS. Citation Format: Rodney Dixon Dorand, Donna Dang, Elizabeth J. Davis, Ben Ho Park. Investigating doxorubicin resistance in fibrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3974.
Translational landscape of glioblastoma immunotherapy for physicians: guiding clinical practice with basic scientific evidence
Authors: Daniel Kreatsoulas, Chelsea Bolyard, Bill X. Wu, Hakan Cam, Pierre Giglio, Zihai Li
Journal: Journal of Hematology & Oncology (2022)

Abstract Despite recent advances in cancer therapeutics, glioblastoma (GBM) remains one of the most difficult cancers to treat in both the primary and recurrent settings. GBM presents a unique therapeutic challenge given the immune-privileged environment of the brain and the aggressive nature of the disease. Furthermore, it can change phenotypes throughout the course of disease—switching between mesenchymal, neural, and classic gene signatures, each with specific markers and mechanisms of resistance. Recent advancements in the field of immunotherapy—which utilizes strategies to reenergize or alter the immune system to target cancer—have shown striking results in patients with many types of malignancy. Immune checkpoint inhibitors, adoptive cellular therapy, cellular and peptide vaccines, and other technologies provide clinicians with a vast array of tools to design highly individualized treatment and potential for combination strategies. There are currently over 80 active clinical trials evaluating immunotherapies for GBM, often in combination with standard secondary treatment options including re-resection and anti-angiogenic agents, such as bevacizumab. This review will provide a clinically focused overview of the immune environment present in GBM, which is frequently immunosuppressive and characterized by M2 macrophages, T cell exhaustion, enhanced transforming growth factor-β signaling, and others. We will also outline existing immunotherapeutic strategies, with a special focus on immune checkpoint inhibitors, chimeric antigen receptor therapy, and dendritic cell vaccines. Finally, we will summarize key discoveries in the field and discuss currently active clinical trials, including combination strategies, burgeoning technology like nucleic acid and nanoparticle therapy, and novel anticancer vaccines. This review aims to provide the most updated summary of the field of immunotherapy for GBM and offer both historical perspective and future directions to help inform clinical practice.
Abstract 5296: Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers
Authors: Kwangil Yim, Nishant Thakur, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar, Yosep Chong, Kyung Jin Seo, Ok Ran Shin
Journal: Cancer Research (2022)

Abstract Purpose: Poly(ADP-ribose) Polymerases-1 (PARP-1) is well known as poor survival factor in various solid cancers and its inhibitors have shown promising results in clinical trials. However, in pancreatic ductal adenocarcinoma (PDAC), there is only one study with good prognostic result. We assessed the prognostic significance of PARP-1 in PDAC Methods: From 1998 to 2020, 194 patients with radical surgery for PDAC were enrolled in Yeouido St. Mary’s hospital (n = 84) and Uijeongbu St. Mary’s hospital (n=110). After making tumor microarray, PARP-1 immunohistochemistry was conducted and we analyzed H score with image analyzer (QuantCenter, 3DHistech, Budapest, Hungary). Results: High expression of PARP1 (OS: p = 0.004, CSS: p = 0.007, DFS: p &amp;lt; 0.001) was good survival factor in univariate analysis. Old age (OS: p = 0.018, CSS: p = 0.041, DFS: p = 0.050 ), high stage (OS: p = 0.004, CSS: p = 0.009, DFS: p = 0.817), lymphatic invasion (OS: p &amp;lt; 0.001, CSS: p &amp;lt; 0.001, DFS: p = 0.001), venous invasion (OS: p &amp;lt; 0.001, CSS: p &amp;lt; 0.001, DFS: p = 0.109), perineural invasion (OS: p &amp;lt; 0.001, CSS: p &amp;lt; 0.001, DFS: p &amp;lt; 0.001) and high grade tumor differentiation (OS: p = 0.005, CSS: p = 0.003, DFS: p = 0.001 ) was poor survival factor in log rank test. In multivariate analysis, PAPR1 was independent good survival factor (OS: p = 0.002, CSS: p = 0.005, DFS: p &amp;lt; 0.001). Conclusion: Our study revealed that PARP1 expression was good survival factor in PDAC unlike other solid cancers. In our observation, studies with larger datasets or on the mechanism of PARP1 in PDAC are necessary in order to use PARP inhibitor in PDAC. Citation Format: Kwangil Yim, Nishant Thakur, Mohammad Rizwan Alam, Jamshid Abdul-Ghafar, Yosep Chong, Kyung Jin Seo, Ok Ran Shin. Poly(ADP-ribose) polymerase-1 expression is a good survival marker in pancreatic cancers, unlike other solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5296.
Abstract LB521: Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis
Authors: Kwangwoo Hwang, SeoHyun Jo, Jieun Choi, Ga-young Choi, Jiseon Choi, Ji-Hye Kwon, Dong-Guk Shin, Jiyeon Kim, Se-Hyuk Kim, Haelee Kim, Ha Yeon Cho, Jung Beom Son, Nam Doo Kim, Hwan Geun Choi, Daekwon Kim, Sunghwan Kim
Journal: Cancer Research (2022)

Abstract FDA approved three RAF inhibitors for the treatment of tumors containing BRAFV600 mutations, but one of the major drawbacks of these type I RAF inhibitors is to activate MAPK signaling pathway, instead of inhibiting signaling, which is referred to as paradoxical activation. Such undesired paradoxical activation not only leads to renewed tumor growth but also spurs additional cancer growth in non-cancerous wild-type BRAF tissue. Plus, these first-generation RAF inhibitors targeting BRAFV600 mutants are unable to inhibit oncogenic RAF dimers. This has led to the development of type II RAF inhibitors such as belvarafenib and day101 to block the activity of multiple forms of RAF while avoiding paradoxical activation. Two lead-like stage compounds 1 and 2 were specifically designed as type II RAF inhibitors to have activity across RAF isoforms including BRAFV600E, BRAF wild-type, and CRAF, showing higher potency than competitors. Compounds 1 and 2 potently inhibited the growth of BRAFV600E melanoma cells and NRAS or KRAS mutant cancer cells. Compounds 1 and 2 promoted the formation of BRAF/CRAF heterodimers by directly binding to the RAF kinase domain like other type II RAF inhibitors and inhibited phosphorylation of downstream effectors MEK and ERK in a dose-dependent manner in RAS mutant cancer cells, suggesting less paradoxical activation liability. Compound 2 showed superior on-target inhibitory activity for BRAFV600E, BRAF wild-type, and CRAF than belvarafenib through RAF immunoprecipitation (IP) kinase assay. Inhibition of the RAF downstream signaling was also confirmed by quantifying the level of phospho-ERK in NRAS or KRAS mutant cancer cells. In HCT116 (KRASG13D) subcutaneous xenograft model, compound 1 showed tumor growth inhibition efficacy, suggesting a potential to address RAS mutant driven- as well as BRAFV600 mutant driven tumors. Also, combination treatment with MEK inhibitor and/or immune checkpoint inhibitor would further improve the therapeutic activity and expand target indication for unmet medical needs. Citation Format: Kwangwoo Hwang, SeoHyun Jo, Jieun Choi, Ga-young Choi, Jiseon Choi, Ji-Hye Kwon, Dong-Guk Shin, Jiyeon Kim, Se-Hyuk Kim, Haelee Kim, Ha Yeon Cho, Jung Beom Son, Nam Doo Kim, Hwan Geun Choi, Daekwon Kim, Sunghwan Kim. Antitumor activity of potent RAF inhibitors in solid tumors with activated RAS-RAF axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB521.
Abstract 2949: Enabling single cell analysis of copy number variation in breast cancer
Authors: Saurabh Parikh, Arnaud Da Cruz Paula, Shirin Issa Bhaloo, Alex Li, Britta Weigelt, Khushali Patel, Ania Wronski, Anup Parikh, Khushali Patel, Jorge Reis-Filho
Journal: Cancer Research (2022)

Abstract Breast cancer is arguably one of the solid tumors most comprehensively analyzed by massively parallel sequencing. Although the repertoire of clonal somatic genetic alterations in primary and metastatic breast cancers has been characterized, a complete characterization of the subclonal genetic alterations present in these cancers, as well as their clonal composition and clonal dynamics remain to be fully defined. Addressing these knowledge gaps is germane to the successful personalization of treatments for breast cancer patients. Single cell sequencing is uncovering many insights into the clonal evolution and heterogeneity of breast cancers and how this can be leveraged for clinical and therapeutic benefit. Bulk next generation sequencing has primarily focused on mutation profiling; however, there are several lines of evidence to demonstrate the biological and clinical importance of accurately detecting copy number alterations. Previous single cell sequencing studies focusing on copy number alterations were based on whole-genome amplification methods or could not concurrently define the repertoire of somatic mutations and copy number alterations in single cells. Here we report on a novel single cell DNA sequencing approach leveraging the Tapestri device and Insights bioinformatic pipeline to detect both copy number alterations and somatic mutations in individual cells derived from breast cancer specimens. The identification of targeted somatic genetic alterations at single cell resolution provides novel insights about the development, progression and therapeutic resistance of breast cancers, and enables the development of novel diagnostic tools and predictive biomarkers. Citation Format: Saurabh Parikh, Arnaud Da Cruz Paula, Shirin Issa Bhaloo, Alex Li, Britta Weigelt, Khushali Patel, Ania Wronski, Anup Parikh, Khushali Patel, Jorge Reis-Filho. Enabling single cell analysis of copy number variation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2949.
Abstract 5474: A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling
Authors: Khuloud Bajbouj, Lina Sahnoon, Abeer AL-Ali, Jasmin Shafarin, Leonie Binder, Reem Abdul Rehman, Rafat El-Awady, Taleb H. Al-Tel
Journal: Cancer Research (2022)

Abstract Background: Mounting epidemiological and experimental evidences strongly suggest that epigenetic processes including histone modifications are involved in the development of drug resistance in breast cancer. Histone deacetylases (HDACs) selective inhibition is an important strategy of anticancer drug discovery field. However, lack of HDACs isozymes selective inhibitors associated with adverse side effects that limits their clinical applications. We have recently reported new and selective HDACs inhibitors displaying varying HDAC isozyme selectivity degrees that resulted in increased histones acetylation and apoptosis induction in cancer cells. In the present study, we investigated molecular mechanisms underlying anticancer potential of these molecules in breast cancer cells. Experimental methods: Proliferation ability, invasion capacity, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) major group’s gene expressions and protein levels, and the gelatinolytic activity of MMPs were analyzed after treatment of MCF-7 and MDA-MB-231 breast cancer cell lines with HDACs inhibitors compounds. Results and Discussions: Two compounds, identified as MAL-4 and MAL-5, were selected based on the half-maximal inhibitory concentration (IC50) in both breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cells with 5 µM MAL-4 and MAL-5 significantly induces TIMP-2 mRNA and protein levels whereas MMP-2 and MMP-9 content and activities were reduced. Further analyses showed that MAL-4 and MAL-5 attenuated invasion capability of breast cancer cells. Conclusion: We have demonstrated that the new compounds can be used as potential lead drug candidates for an effective anti-metastatic therapy mediated by HDAC inhibition in breast cancer. Citation Format: Khuloud Bajbouj, Lina Sahnoon, Abeer AL-Ali, Jasmin Shafarin, Leonie Binder, Reem Abdul Rehman, Rafat El-Awady, Taleb H. Al-Tel. A new class of histone deacetylase inhibitors alleviate breast cancer cells growth and invasion capacity by targeting TIMP/MMP signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5474.
Abstract 3141: Toll-like receptor 4 knockout promotes cutaneous tumorigenesis in mice lack of <i>Ikka</i> heterozygous loss in keratinocytes
Authors: Amit Kumar Singh
Journal: Cancer Research (2022)

Abstract Role of recognizing pathogen-associated molecular patterns in skin carcinogenesis has not been extensively studied. Toll-like receptor 4 (TLR4) recognizes gram-negative lipopolysaccharide. To explore the impact of interplay between TLR4-regulated microbiota and host epithelial cells on tumorigenesis, we adopted a mouse model that expresses hemizygous Ikkα gene induced by a keratin 5 Cre (K5.Cre, IkkααKC/+). IkkααKC mice die within 3 weeks after birth. Inducible Ikkα ablation mediated by K15.CrePR1 or K5.CreER results in spontaneous skin tumors. We found an increased incidence of spontaneous skin tumors in Tlr4-/-;IkkααKC/+ mice compared to Tlr4-/- or IkkααKC/+ mice. We detected markedly elevated bacteria numbers on the surface of skin tumors compared to the adjacent skin. Interestingly, the oral cavity of Tlr4-/-;IkkααKC/+ mice showed an elevated proportion of gram-negative bacteria compared to Tlr4-/- or IkkααKC/+ mice. To further determine the effect of bone marrow (BM)-derived hemopoietic cells on tumorigenesis, we performed BM transplant experiments. IkkααKC/+ mice with Tlr4-/- BM developed more cutaneous skin tumors than IkkααKC/+ mice with WT BM. Based on these findings, we hypothesized that Tlr4-/- hemopoietic cells regulate microbiota, which further results in altered skin carcinogenesis. We are revealing the detailed mechanism of how Tlr4-/- hemopoietic cells contribute to microbiota changes and tumorigenic promotion. Citation Format: Amit Kumar Singh. Toll-like receptor 4 knockout promotes cutaneous tumorigenesis in mice lack of Ikka heterozygous loss in keratinocytes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3141.
Abstract 2720: Unbiased identification of RNA splicing-defined patient populations in lung adenocarcinoma
Authors: Audrey Crowther
Journal: Cancer Research (2022)

Abstract Aberrant alternative splicing is known to directly contribute to tumor progression in lung adenocarcinoma (LUAD). While the action of individual splicing variants as cancer drivers have been characterized in LUAD, the global splicing landscape and how that corresponds to patient prognosis is poorly understood. Using whole transcriptome RNA-Seq data provided from The Cancer Genome Atlas (TCGA), we applied a new computational pipeline, OncoSplice, to identify potentially novel prognostic disease splicing subtypes and elucidate the biological mechanisms underlying these subtypes. OncoSplice identified over 30 novel splicing-defined subtypes of LUAD, several of which correlate with worse patient survival. Additionally, we identified patient clusters that were significantly enriched in mutations for RNA binding proteins, such as Cap Methyltransferase 2 (CMTR2) and RNA Binding Motif 10 (RBM10). More specifically, mutations in the splicing factor RBM10 were found to be enriched but not requisite for the dominant poor prognosis splicing subtype in LUAD. In non-mutant patients within this subset, RBM10 gene expression downregulation was induced, mimicking the mutation phenotype. Hence, we find alternative non-genetic pathways for impacting splicing in LUAD that leads to poor prognosis through disruption of canonical splicing. Citation Format: Audrey Crowther. Unbiased identification of RNA splicing-defined patient populations in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2720.